CN108586450B - Recrystallization purification method of choline M receptor anticaking agent - Google Patents
Recrystallization purification method of choline M receptor anticaking agent Download PDFInfo
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Abstract
The invention provides a recrystallization purification method of a choline M receptor anticaking agent, which comprises the following steps: (1) heating the aclidinium bromide crude product and DMF to 90-130 ℃, stirring, dissolving and clarifying; (2) cooling and stirring the solution obtained in the step (1); (3) and (3) cooling the solution obtained in the step (2), then dripping an anti-solvent, then continuously cooling, stirring, filtering and drying in vacuum to obtain the pure aclidinium bromide. The method can effectively reduce impurities in the finished product of the aclidinium bromide, control DMF residue, and is simple in reaction operation and easy for industrial production.
Description
Technical Field
The invention relates to the technical field of medicine synthesis, in particular to a recrystallization purification method of a choline M receptor anticaking agent.
Background
Chronic obstructive pulmonary disease is a common respiratory disease, a preventable and treatable disease characterized by airflow limitation that is not completely reversible and progresses progressively. The aclidinium bromide belongs to an inhalant long-acting M choline resistant drug which is a selective M3 receptor antagonist and can be used for treating chronic obstructive pulmonary disease related bronchospasm (lung airway narrowing) including chronic bronchitis and emphysema for a long time. Aclidinium bromide is the third marketed anticholinergic bronchodilator after ipratropium bromide and tiotropium bromide, and its onset speed is faster than tiotropium bromide, close to ipratropium bromide. The aclidinium bromide has high selectivity on M3 cholinergic receptors, can be combined with M2 and M3 receptors after entering a body, but is combined with M3 receptors more firmly, the half life of the aclidinium bromide is 6 times of that of the M2 receptors, the aclidinium bromide belongs to long-acting cholinergic receptor antagonists, and adverse reactions such as tachycardia and the like of the aclidinium bromide for resisting the M2 receptors are relatively less. In addition, after the tertiary amine group is quaternized by the aclidinium bromide, the oral bioavailability and the capability of penetrating through a blood brain barrier are reduced, and after the drug is taken by inhalation, the systemic adverse reaction is less.
Aclidinium bromide, chemical name: (3R) - (2-hydroxy-2, 2-dithien-2-yl acetoxyl) -1- (3-phenoxypropyl) -1-aza-onium bicyclo [2.2.2] octane bromide, relating to the synthesis of aclidinium bromide, the synthetic route in the prior art mainly comprises the following five synthetic methods:
the preparation method of the aclidinium bromide disclosed in the US patent 6750226(B2) or the Chinese patent CN1272334C comprises the following synthetic route:
the method takes 2-thienyl glyoxylic acid as a starting material, and comprises the steps of carrying out chlorination reaction on oxalyl chloride, esterifying the chlorinated glyoxylic acid with R-quininol, carrying out Grignard reaction on the esterified quininol and 2-bromomagnesium thiophene, and finally carrying out quaternization reaction to obtain the product.
The preparation method of aclidinium bromide disclosed in the chemical industry trade of China (sixth 6 months in 2013) comprises the following specific synthetic route:
the method comprises the steps of taking 2-bromothiophene as an initial raw material, reacting with magnesium to generate a Grignard reagent, carrying out Grignard reaction with dimethyl oxalate, carrying out ester exchange reaction with R-quinine alcohol, and carrying out quaternary amination reaction to obtain aclidinium bromide.
The preparation method of aclidinium bromide disclosed in Chinese patent CN104478871A has the following specific synthetic route:
the method comprises the steps of taking R-quininol as a starting material, carrying out ester reaction with oxalyl chloromethyl ester, carrying out Grignard reaction with 2-magnesium bromothiophene, and carrying out quaternization reaction to obtain aclidinium bromide.
The preparation method of aclidinium bromide disclosed in Chinese patent CN103755699A has the following synthetic route:
the method comprises the steps of taking R-quininol as a starting material, carrying out ester reaction with oxalyl chloromethyl ester, carrying out Grignard reaction with 2-magnesium bromothiophene, and carrying out quaternization reaction to obtain aclidinium bromide.
Disclosure of Invention
Although the method for synthesizing the choline M receptor anticaking agent aclidinium bromide does not embody a recrystallization purification process, CN106831756 discloses that absolute ethyl alcohol is used as a recrystallization solvent to purify a crude product of aclidinium bromide, the research of technical personnel of the invention finds that the crude product of aclidinium bromide cannot be dissolved by using a large amount of heated ethanol (70 times), the recrystallization operation cannot be carried out, and the product purity is greatly influenced. According to the invention, researches show that the solubility of the crude adefovir dipivoxil in most solvents is not ideal, and the crude adefovir dipivoxil can be dissolved and clarified only in heated DMF and DMSO, but the boiling point of DMSO is very high, so that the solvent residues after recrystallization are overproof. Although the invention also has the problem that the solvent residue exceeds the standard by using the DMF recrystallization, the impurities and the DMF solvent residue can be controlled at a lower level after the recrystallization purification method of the invention.
The invention aims to provide a recrystallization purification method of a choline M receptor anticaking agent aclidinium bromide crude product, which can effectively reduce impurities of an aclidinium bromide finished product, control DMF (dimethyl formamide) residue, has simple reaction operation and is easy for industrial production.
The technical scheme for realizing the purpose is as follows:
the invention provides a recrystallization purification method of choline M receptor anticaking agent aclidinium bromide, which comprises the following steps:
(1) heating the crude product of aclidinium bromide and DMF, stirring, dissolving and clarifying;
(2) cooling the solution obtained in the step (1), and keeping the temperature and stirring;
(3) and (3) cooling the solution obtained in the step (2), dripping an anti-solvent, cooling, stirring, filtering and vacuum drying.
Preferably, in the step (1), the ratio of the DMF to the crude adefovir dipivoxil is 8-15 ml: 1g, preferably 10 ml: 1g of a compound;
preferably, in the step (1), the heating is carried out to 90-130 ℃, preferably to 90-100 ℃;
preferably, in the step (1), the stirring time is 0.5-1.5 h, preferably 1 h.
Preferably, the step (2) further comprises the step of cooling the solution obtained in the step (1) and then adding aclidinium bromide seed crystals; preferably, the addition amount of the aclidinium bromide seed crystal is 1-5% of the weight of the solution obtained in the step (1);
preferably, the temperature of the solution obtained in the step (1) is reduced to 60-80 ℃, preferably 75-80 ℃;
preferably, the heat preservation stirring time is 1-5h, preferably 1 h.
Preferably, in the step (3), the solution obtained in the step (2) is cooled to 40-80 ℃ and then is dripped into the anti-solvent, and preferably, the temperature is cooled to 40-45 ℃ and then the anti-solvent is dripped into the solution;
preferably, the antisolvent is one or more selected from dichloromethane, ethyl acetate, acetonitrile and tetrahydrofuran;
preferably, after the anti-solvent is dropped, the temperature is continuously reduced to 0-40 ℃, and preferably 20-30 ℃;
preferably, the stirring time is 0.5-1.5 h, preferably 1 h;
preferably, the filtration is vacuum filtration;
preferably, the temperature of the vacuum drying is 55-65 ℃, and preferably 60 ℃; preferably, the vacuum degree is-0.8 to-0.1 MPa.
Preferably, the recrystallization purification method of the choline M receptor anticaking agent aclidinium bromide comprises the following steps:
(1) heating the aclidinium bromide crude product and DMF to 90-100 ℃, stirring for 1h, dissolving and clarifying; wherein the ratio of the DMF to the crude adefovir dipivoxil is 10 ml: 1g of a compound;
(2) cooling the solution obtained in the step (1) to 75-80 ℃, adding an aclidinium bromide seed crystal, and stirring for 1 h; wherein the addition amount of the aclidinium bromide seed crystal is 1-5% of the weight of the solution obtained in the step (1);
(3) and (3) cooling the solution obtained in the step (2) to 40-45 ℃, then dripping an anti-solvent, then continuously cooling to 20-30 ℃, stirring for 1h, carrying out vacuum filtration, and carrying out vacuum drying at 60 ℃ and-0.8-0.1 Mpa to obtain the pure aclidinium bromide.
The recrystallization purification method of the crude aclidinium bromide provided by the invention can better reduce the impurity level of aclidinium bromide and improve the quality of finished products, and particularly, the DMF residue of the finished aclidinium bromide products is reduced to accord with the ICH standard (less than 0.088%) by growing crystals at a certain temperature and increasing particles in the recrystallization process, the yield of the recrystallized products can reach 95% at most, the reaction operation is simple, and the industrial production is easy.
Drawings
Embodiments of the invention are described in detail below with reference to the attached drawing figures, wherein:
FIG. 1 is a powder diffraction XRD pattern of the finished aclidinium bromide product of the present invention.
Detailed Description
The invention is illustrated below with reference to specific examples. It will be understood by those skilled in the art that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention in any way.
The experimental procedures in the following examples are conventional unless otherwise specified. The medicinal materials, reagent materials, etc. used IN the following examples are commercially available products unless otherwise specified, and the starting material 2, 2-dithienyl-2-hydroxyacetic acid was prepared according to Indian patent IN2005DN 01810.
The apparatus used was: nuclear magnetic resonance (Bruker AVANCE III HD 500); mass spectrometry (LTQ Orbitrap Elite); liquid chromatography (Agilent 1260).
The following liquid phase detection methods are adopted in the invention:
a chromatographic column: waters Xbridge 5 μm 4.6 x 250mm
Mobile phase: a: 0.1% sodium heptanesulfonate (ph 3.2); b: acetonitrile
| Time (min) | A％ | B％ |
| 0 | 73 | 27 |
| 3 | 69 | 27 |
| 23 | 49 | 51 |
| 43 | 35 | 65 |
| 55 | 32 | 68 |
| 55.1 | 73 | 27 |
| 60 | 73 | 27 |
Flow rate: 1.0ml/min
Column temperature: 30 deg.C
Detection wavelength: 238nm
Sample introduction volume: 10 μ L
Diluting liquid: acetonitrile
The DMF solvent residue gas phase detection method of the invention comprises the following steps:
example 1: recrystallization purification of the crude product of aclidinium bromide
Preparation of 2, 2-dithienyl-2-hydroxyacetic acid-R-quinuclidin-3-yl ester
Adding 50g of 2, 2-dithienyl-2-glycolic acid (0.21mol) and 500ml of DMF (dimethyl formamide) into a reaction bottle, slowly adding 37.45g of CDI (0.23mol) solid, stirring for 1 hour at 15-25 ℃, then adding 26.7g of R-3-quininol (0.21mol), stirring for 12 hours at 30-35 ℃, adopting TLC to monitor the complete reaction of the raw materials, cooling to 0-5 ℃ in an ice bath, slowly dropping 500ml of water, stirring for 0.5 hour at 0-10 ℃ after dropping, filtering, and drying in vacuum at 60 ℃ and-0.08 MPa to obtain 58.1g of similar white solid with the yield of 79.9%, wherein the purity of HPLC: 98.5 percent.
1HNMR(DMSO-d6)：δppm 1.2-1.34(m，1H)，1.37-1.68(m，3H)，1.87-1.95(m，1H)，2.34-2.75(m，5H)，3.04-3.15(ddd，1H)，4.76-4.87(m，1H)，6.98-7.04(m，2H)，7.09-7.12(m，2H)，7.37(brs，1H)，7.46-7.54(m，2H).MS(ESI)350m/z(M+H)+
2. Preparation of the crude product of aclidinium bromide
58.1g of 2, 2-dithienyl-2-hydroxyacetic acid-R-quinine-3-yl ester (0.17mol), 43g of 3-phenoxybromopropane (0.2mol) and 600ml of acetonitrile are added into a reaction bottle, reflux reaction is carried out for 3 hours, the temperature is reduced to 20-30 ℃, and after filtration, vacuum drying is carried out at 50 ℃ to obtain 87.3g of white solid, the yield is 93%, and the purity is 98.5%.
3. Recrystallization purification of the crude product of aclidinium bromide
Adding 4g of crude aclidinium bromide and 40ml of DMF (dimethyl formamide) into a reaction bottle, heating to 90-100 ℃, stirring for 1 hour, dissolving and clarifying, cooling to 70-80 ℃, adding aclidinium bromide accounting for 1% of the weight of the solution as seed crystals, continuously stirring for 1 hour, cooling to 40-45 ℃, dripping 40ml of ethyl acetate, continuously cooling to 20-30 ℃ after dripping, stirring for 1 hour, filtering, and drying in vacuum at 60 ℃ and-0.09 MPa to obtain 3.8g of white solid, wherein the yield is 95%, the purity is 99.9%, and the DMF residue is 0.05%.
1HNMR(DMSO-d6)：δppm 1.75(d，2H)，1.96(dd，2H)，2.14(d，2H)，2.33(s，1H)，3.21(d，1H)，3.36-3.78(m，6H)，3.93-4.11(m，3H)，5.25(s，1H)，6.98(dd，5H)，7.19(s，2H)，7.32(t，2H)，7.50(s，1H)，7.53(d，2H)。MS(ESI)484m/z(M-Br)+。
Example 2: recrystallization purification of the crude product of aclidinium bromide
Preparation of 2, 2-dithienyl-2-hydroxyacetic acid-R-quinuclidin-3-yl ester
Adding 50g of 2, 2-dithienyl-2-glycolic acid (0.21mol) and 500ml of DMF (dimethyl formamide) into a reaction bottle, slowly adding 37.45g of CDI (0.23mol) solid, stirring at 15-25 ℃ for 1 hour, then adding 26.7g of R-3-quininol (0.21mol), stirring at 30-35 ℃ for 12 hours, adopting TLC to monitor the complete reaction of the raw materials, cooling to 0-5 ℃ in an ice bath, slowly dropping 500ml of water, stirring at 0-10 ℃ for 0.5 hour after dropping, filtering, and drying in vacuum at 60 ℃ to obtain 58.1g of white-like solid with the yield of 79.9 percent and the purity of HPLC: 98.5 percent.
1HNMR(DMSO-d6)：δppm 1.2-1.34(m，1H)，1.37-1.68(m，3H)，1.87-1.95(m，1H)，2.34-2.75(m，5H)，3.04-3.15(ddd，1H)，4.76-4.87(m，1H)，6.98-7.04(m，2H)，7.09-7.12(m，2H)，7.37(brs，1H)，7.46-7.54(m，2H).MS(ESI)350m/z(M+H)+
2. Preparation of the crude product of aclidinium bromide
58.1g of 2, 2-dithienyl-2-hydroxyacetic acid-R-quinine-3-yl ester (0.17mol), 43g of 3-phenoxybromopropane (0.2mol) and 600ml of acetonitrile are added into a reaction bottle, reflux reaction is carried out for 3 hours, the temperature is reduced to 20-30 ℃, and after filtration, vacuum drying is carried out at 50 ℃ to obtain 87.3g of white solid, the yield is 93%, and the purity is 98.5%.
3. Recrystallization purification of the crude product of aclidinium bromide
Adding 4g of crude aclidinium bromide and 32ml of DMF (dimethyl formamide) into a reaction bottle, heating to 120-130 ℃, stirring for 1 hour, dissolving and clarifying, cooling to 60-65 ℃, adding aclidinium bromide accounting for 1% of the weight of the solution as seed crystals, continuously stirring for 1 hour, cooling to 40-45 ℃, dropping 32ml of acetonitrile, continuously cooling to 20-30 ℃ after dropping, stirring for 1 hour, filtering, and drying in vacuum at 60 ℃ and-0.09 MPa to obtain 3.3g of white solid, wherein the yield is 82.5%, the purity is 99.8%, and the DMF residue is 0.03%. The powder diffraction XRD pattern is shown in figure 1.
Example 3: recrystallization purification of the crude product of aclidinium bromide
Preparation of 2, 2-dithienyl-2-hydroxyacetic acid-R-quinuclidin-3-yl ester
Adding 50g of 2, 2-dithienyl-2-glycolic acid (0.21mol) and 500ml of DMF (dimethyl formamide) into a reaction bottle, slowly adding 37.45g of CDI (0.23mol) solid, stirring for 1 hour at 15-25 ℃, then adding 26.7g of R-3-quininol (0.21mol), stirring for 12 hours at 30-35 ℃, adopting TLC to monitor the complete reaction of the raw materials, cooling to 0-5 ℃ in an ice bath, slowly dropping 500ml of water, stirring for 0.5 hour at 0-10 ℃ after dropping, filtering, and drying in vacuum at 60 ℃ and-0.09 MPa to obtain 58.1g of similar white solid with the yield of 79.9%, wherein the purity of HPLC: 98.5 percent.
1HNMR(DMSO-d6)：δppm 1.2-1.34(m，1H)，1.37-1.68(m，3H)，1.87-1.95(m，1H)，2.34-2.75(m，5H)，3.04-3.15(ddd，1H)，4.76-4.87(m，1H)，6.98-7.04(m，2H)，7.09-7.12(m，2H)，7.37(brs，1H)，7.46-7.54(m，2H).MS(ESI)350m/z(M+H)+
2. Preparation of the crude product of aclidinium bromide
58.1g of 2, 2-dithienyl-2-hydroxyacetic acid-R-quinine-3-yl ester (0.17mol), 43g of 3-phenoxybromopropane (0.2mol) and 600ml of acetonitrile are added into a reaction bottle, reflux reaction is carried out for 3 hours, the temperature is reduced to 20-30 ℃, and after filtration, vacuum drying is carried out at 50 ℃ to obtain 87.3g of white solid, the yield is 93%, and the purity is 98.5%.
3. Recrystallization purification of the crude product of aclidinium bromide
Adding 4g of crude aclidinium bromide and 60ml of DMF (dimethyl formamide) into a reaction bottle, heating to 90-100 ℃, stirring for 1 hour, dissolving and clarifying, cooling to 60-65 ℃, adding aclidinium bromide accounting for 3% of the weight of the solution as seed crystals, continuously stirring for 1 hour, cooling to 40-45 ℃, dripping 60ml of dichloromethane, continuously cooling to 20-30 ℃ after dripping, stirring for 1 hour, filtering, and drying in vacuum at 60 ℃ and-0.08 MPa to obtain 3.4g of white solid, wherein the yield is 85%, the purity is 99.9%, and the DMF residue is 0.08%.
Example 4: recrystallization purification of the crude product of aclidinium bromide
Preparation of 2, 2-dithienyl-2-hydroxyacetic acid-R-quinuclidin-3-yl ester
Adding 50g of 2, 2-dithienyl-2-glycolic acid (0.21mol) and 500ml of DMF (dimethyl formamide) into a reaction bottle, slowly adding 37.45g of CDI (0.23mol) solid, stirring for 1 hour at 15-25 ℃, then adding 26.7g of R-3-quininol (0.21mol), stirring for 12 hours at 30-35 ℃, adopting TLC to monitor the complete reaction of the raw materials, cooling to 0-5 ℃ in an ice bath, slowly dropping 500ml of water, stirring for 0.5 hour at 0-10 ℃ after dropping, filtering, and drying in vacuum at 60 ℃ and-0.01 MPa to obtain 58.1g of similar white solid with the yield of 79.9%, wherein the purity of HPLC: 98.5 percent.
1HNMR(DMSO-d6)：δppm 1.2-1.34(m，1H)，1.37-1.68(m，3H)，1.87-1.95(m，1H)，2.34-2.75(m，5H)，3.04-3.15(ddd，1H)，4.76-4.87(m，1H)，6.98-7.04(m，2H)，7.09-7.12(m，2H)，7.37(brs，1H)，7.46-7.54(m，2H).MS(ESI)350m/z(M+H)+
2. Preparation of the crude product of aclidinium bromide
58.1g of 2, 2-dithienyl-2-hydroxyacetic acid-R-quinine-3-yl ester (0.17mol), 43g of 3-phenoxybromopropane (0.2mol) and 600ml of acetonitrile are added into a reaction bottle, reflux reaction is carried out for 3 hours, the temperature is reduced to 20-30 ℃, and after filtration, vacuum drying is carried out at 50 ℃ to obtain 87.3g of white solid, the yield is 93%, and the purity is 98.5%.
3. Recrystallization purification of the crude product of aclidinium bromide
Adding 4g of crude aclidinium bromide and 40ml of DMF (dimethyl formamide) into a reaction bottle, heating to 90-100 ℃, stirring for 1 hour, dissolving and clarifying, cooling to 70-80 ℃, adding aclidinium bromide accounting for 5% of the weight of the solution as a seed crystal, continuously stirring for 1 hour, cooling to 40-45 ℃, dripping 40ml of ethyl acetate, continuously cooling to 0-5 ℃ after dripping, stirring for 1 hour, filtering, and drying in vacuum at 60 ℃ and-0.01 MPa to obtain 3.8g of white solid, wherein the yield is 95%, the purity is 99.9%, and the DMF residue is 0.06%.
Example 5: recrystallization purification of the crude product of aclidinium bromide
Preparation of 2, 2-dithienyl-2-hydroxyacetic acid-R-quinuclidin-3-yl ester
Adding 50g of 2, 2-dithienyl-2-glycolic acid (0.21mol) and 500ml of DMF (dimethyl formamide) into a reaction bottle, slowly adding 37.45g of CDI (0.23mol) solid, stirring for 1 hour at 15-25 ℃, then adding 26.7g of R-3-quininol (0.21mol), stirring for 12 hours at 30-35 ℃, adopting TLC to monitor the complete reaction of the raw materials, cooling to 0-5 ℃ in an ice bath, slowly dropping 500ml of water, stirring for 0.5 hour at 0-10 ℃ after dropping, filtering, and drying in vacuum at 60 ℃ and-0.09 MPa to obtain 58.1g of similar white solid with the yield of 79.9%, wherein the purity of HPLC: 98.5 percent.
1HNMR(DMSO-d6)：δppm 1.2-1.34(m，1H)，1.37-1.68(m，3H)，1.87-1.95(m，1H)，2.34-2.75(m，5H)，3.04-3.15(ddd，1H)，4.76-4.87(m，1H)，6.98-7.04(m，2H)，7.09-7.12(m，2H)，7.37(brs，1H)，7.46-7.54(m，2H).MS(ESI)350m/z(M+H)+
2. Preparation of the crude product of aclidinium bromide
58.1g of 2, 2-dithienyl-2-hydroxyacetic acid-R-quinine-3-yl ester (0.17mol), 43g of 3-phenoxybromopropane (0.2mol) and 600ml of acetonitrile are added into a reaction bottle, reflux reaction is carried out for 3 hours, the temperature is reduced to 20-30 ℃, and after filtration, vacuum drying is carried out at 50 ℃ to obtain 87.3g of white solid, the yield is 93%, and the purity is 98.5%.
3. Recrystallization purification of the crude product of aclidinium bromide
Adding 4g of crude aclidinium bromide and 40ml of DMF (dimethyl formamide) into a reaction bottle, heating to 90-100 ℃, stirring for 1 hour, dissolving and clarifying, cooling to 75-80 ℃, adding aclidinium bromide accounting for 5% of the weight of the solution as seed crystals, continuing stirring for 1 hour, cooling to 40-45 ℃, dropping 40ml of acetonitrile, continuing cooling to 35-40 ℃ after dropping, stirring for 1 hour, filtering, and performing vacuum drying at 60 ℃ and-0.09 MPa to obtain 2.6g of white solid, wherein the yield is 65%, the purity is 99.8%, and the DMF residue is 0.08%.
Example 6: recrystallization purification of the crude product of aclidinium bromide
Preparation of 2, 2-dithienyl-2-hydroxyacetic acid-R-quinuclidin-3-yl ester
Adding 50g of 2, 2-dithienyl-2-glycolic acid (0.21mol) and 500ml of DMF (dimethyl formamide) into a reaction bottle, slowly adding 37.45g of CDI (0.23mol) solid, stirring for 1 hour at 15-25 ℃, then adding 26.7g of R-3-quininol (0.21mol), stirring for 12 hours at 30-35 ℃, adopting TLC to monitor the complete reaction of the raw materials, cooling to 0-5 ℃ in an ice bath, slowly dropping 500ml of water, stirring for 0.5 hour at 0-10 ℃ after dropping, filtering, and drying in vacuum at 60 ℃ and-0.09 MPa to obtain 58.1g of similar white solid with the yield of 79.9%, wherein the purity of HPLC: 98.5 percent.
1HNMR(DMSO-d6)：δppm 1.2-1.34(m，1H)，1.37-1.68(m，3H)，1.87-1.95(m，1H)，2.34-2.75(m，5H)，3.04-3.15(ddd，1H)，4.76-4.87(m，1H)，6.98-7.04(m，2H)，7.09-7.12(m，2H)，7.37(brs，1H)，7.46-7.54(m，2H).MS(ESI)350m/z(M+H)+
2. Preparation of the crude product of aclidinium bromide
58.1g of 2, 2-dithienyl-2-hydroxyacetic acid-R-quinine-3-yl ester (0.17mol), 43g of 3-phenoxybromopropane (0.2mol) and 600ml of acetonitrile are added into a reaction bottle, reflux reaction is carried out for 3 hours, the temperature is reduced to 20-30 ℃, and after filtration, vacuum drying is carried out at 50 ℃ to obtain 87.3g of white solid, the yield is 93%, and the purity is 98.5%.
3. Recrystallization purification of the crude product of aclidinium bromide
Adding 4g of crude aclidinium bromide and 40ml of DMF (dimethyl formamide) into a reaction bottle, heating to 90-100 ℃, stirring for 1 hour, dissolving and clarifying, cooling to 60-65 ℃, adding aclidinium bromide accounting for 1% of the weight of the solution as seed crystals, continuing stirring for 1 hour, then cooling to 40-45 ℃, dripping 40ml of tetrahydrofuran, continuing cooling to 20-30 ℃ after dripping, stirring for 1 hour, filtering, and performing vacuum drying at 60 ℃ and-0.09 MPa to obtain 3.2g of white solid, wherein the yield is 80%, the purity is 99.9%, and the DMF residue is 0.07%.
Comparative example 1: purification of crude aclidinium bromide
Preparation of 2, 2-dithienyl-2-hydroxyacetic acid-R-quinuclidin-3-yl ester
Adding 50g of 2, 2-dithienyl-2-glycolic acid (0.21mol) and 500ml of DMF (dimethyl formamide) into a reaction bottle, slowly adding 37.45g of CDI (0.23mol) solid, stirring at 15-25 ℃ for 1 hour, then adding 26.7g of R-3-quininol (0.21mol), stirring at 30-35 ℃ for 12 hours, adopting TLC to monitor the complete reaction of the raw materials, cooling to 0-5 ℃ in an ice bath, slowly dropping 500ml of water, stirring at 0-10 ℃ for 0.5 hour after dropping, filtering, and drying in vacuum at 60 ℃ to obtain 58.1g of white-like solid with the yield of 79.9 percent and the purity of HPLC: 98.5 percent.
1HNMR(DMSO-d6)：δppm 1.2-1.34(m，1H)，1.37-1.68(m，3H)，1.87-1.95(m，1H)，2.34-2.75(m，5H)，3.04-3.15(ddd，1H)，4.76-4.87(m，1H)，6.98-7.04(m，2H)，7.09-7.12(m，2H)，7.37(brs，1H)，7.46-7.54(m，2H).MS(ESI)350m/z(M+H)+
2. Preparation of the crude aclidinium bromide
58.1g of 2, 2-dithienyl-2-hydroxyacetic acid-R-quinine-3-yl ester (0.17mol), 43g of 3-phenoxybromopropane (0.2mol) and 600ml of acetonitrile are added into a reaction bottle, reflux reaction is carried out for 3 hours, the temperature is reduced to 20-30 ℃, and after filtration, vacuum drying is carried out at 50 ℃ to obtain 87.3g of white solid, the yield is 93%, and the purity is 98.5%.
3. Purification of the crude aclidinium bromide
Adding 4g of crude aclidinium bromide and 20ml of DMF into a reaction bottle, stirring for 1 hour at 120-130 ℃, dissolving the aclidinium bromide to be clear, cooling to 70-80 ℃, stirring for 1 hour, cooling to 40-45 ℃ again, dropping 20ml of ethyl acetate, continuing cooling to 20-30 ℃ after dropping, stirring for 1 hour, filtering, and drying in vacuum at 60 ℃ to obtain 3.9g of white solid, wherein the yield is 97.5%, the purity is 99.1%, and the DMF residue is 0.29%.
Comparative example 2: purification of crude aclidinium bromide
Preparation of 2, 2-dithienyl-2-hydroxyacetic acid-R-quinuclidin-3-yl ester
Adding 50g of 2, 2-dithienyl-2-glycolic acid (0.21mol) and 500ml of DMF (dimethyl formamide) into a reaction bottle, slowly adding 37.45g of CDI (0.23mol) solid, stirring at 15-25 ℃ for 1 hour, then adding 26.7g of R-3-quininol (0.21mol), stirring at 30-35 ℃ for 12 hours, adopting TLC to monitor the complete reaction of the raw materials, cooling to 0-5 ℃ in an ice bath, slowly dropping 500ml of water, stirring at 0-10 ℃ for 0.5 hour after dropping, filtering, and drying in vacuum at 60 ℃ to obtain 58.1g of white-like solid with the yield of 79.9 percent and the purity of HPLC: 98.5 percent.
1HNMR(DMSO-d6)：δppm 1.2-1.34(m，1H)，1.37-1.68(m，3H)，1.87-1.95(m，1H)，2.34-2.75(m，5H)，3.04-3.15(ddd，1H)，4.76-4.87(m，1H)，6.98-7.04(m，2H)，7.09-7.12(m，2H)，7.37(brs，1H)，7.46-7.54(m，2H).MS(ESI)350m/z(M+H)+
2. Preparation of the crude aclidinium bromide
58.1g of 2, 2-dithienyl-2-hydroxyacetic acid-R-quinine-3-yl ester (0.17mol), 43g of 3-phenoxybromopropane (0.2mol) and 600ml of acetonitrile are added into a reaction bottle, reflux reaction is carried out for 3 hours, the temperature is reduced to 20-30 ℃, and after filtration, vacuum drying is carried out at 50 ℃ to obtain 87.3g of white solid, the yield is 93%, and the purity is 98.5%.
3. Purification of the crude aclidinium bromide
Adding 4g of crude aclidinium bromide and 80ml of DMF (dimethyl formamide) into a reaction bottle, stirring for 1 hour at 100-110 ℃, dissolving and clarifying, cooling to 60-65 ℃, adding aclidinium bromide accounting for 1% of the weight of the solution as seed crystals, stirring for 1 hour, then cooling to 40-45 ℃, dropwise adding 80ml of ethyl acetate, continuously cooling to 20-30 ℃ after dropwise adding, stirring for 1 hour, filtering, and drying in vacuum at 60 ℃ and-0.09 MPa to obtain 3.4g of white solid, wherein the yield is 85%, the purity is 99.9%, and the DMF residue is 0.54%.
Comparative example 3: purification of crude aclidinium bromide
Preparation of 2, 2-dithienyl-2-hydroxyacetic acid-R-quinuclidin-3-yl ester
Adding 50g of 2, 2-dithienyl-2-glycolic acid (0.21mol) and 500ml of DMF (dimethyl formamide) into a reaction bottle, slowly adding 37.45g of CDI (0.23mol) solid, stirring at 15-25 ℃ for 1 hour, then adding 26.7g of R-3-quininol (0.21mol), stirring at 30-35 ℃ for 12 hours, adopting TLC to monitor the complete reaction of the raw materials, cooling to 0-5 ℃ in an ice bath, slowly dropping 500ml of water, stirring at 0-10 ℃ for 0.5 hour after dropping, filtering, and drying in vacuum at 60 ℃ to obtain 58.1g of white-like solid with the yield of 79.9 percent and the purity of HPLC: 98.5 percent.
1HNMR(DMSO-d6)：δppm 1.2-1.34(m，1H)，1.37-1.68(m，3H)，1.87-1.95(m，1H)，2.34-2.75(m，5H)，3.04-3.15(ddd，1H)，4.76-4.87(m，1H)，6.98-7.04(m，2H)，7.09-7.12(m，2H)，7.37(brs，1H)，7.46-7.54(m，2H).MS(ESI)350m/z(M+H)+
2. Preparation of the crude aclidinium bromide
58.1g of 2, 2-dithienyl-2-hydroxyacetic acid-R-quinine-3-yl ester (0.17mol), 43g of 3-phenoxybromopropane (0.2mol) and 600ml of acetonitrile are added into a reaction bottle, reflux reaction is carried out for 3 hours, the temperature is reduced to 20-30 ℃, and after filtration, vacuum drying is carried out at 50 ℃ to obtain 87.3g of white solid, the yield is 93%, and the purity is 98.5%.
3. Purification of the crude aclidinium bromide
Adding 4g of crude aclidinium bromide and 40ml of DMF (dimethyl formamide) into a reaction bottle, stirring for 1 hour at 90-100 ℃, dissolving and clarifying, cooling to 85-90 ℃, adding aclidinium bromide accounting for 1% of the weight of the solution as a seed crystal, stirring for 1 hour, then cooling to 40-45 ℃ again, dripping 40ml of dichloromethane, cooling to 20-30 ℃ after dripping, stirring for 1 hour, filtering, and drying in vacuum at 60 ℃ and-0.09 MPa to obtain 3.6g of white solid, wherein the yield is 90%, the purity is 99.8%, and the DMF residue is 0.18%.
Comparative example 4: purification of crude aclidinium bromide
Preparation of 2, 2-dithienyl-2-hydroxyacetic acid-R-quinuclidin-3-yl ester
Adding 50g of 2, 2-dithienyl-2-glycolic acid (0.21mol) and 500ml of DMF (dimethyl formamide) into a reaction bottle, slowly adding 37.45g of CDI (0.23mol) solid, stirring at 15-25 ℃ for 1 hour, then adding 26.7g of R-3-quininol (0.21mol), stirring at 30-35 ℃ for 12 hours, adopting TLC to monitor the complete reaction of the raw materials, cooling to 0-5 ℃ in an ice bath, slowly dropping 500ml of water, stirring at 0-10 ℃ for 0.5 hour after dropping, filtering, and drying in vacuum at 60 ℃ to obtain 58.1g of white-like solid with the yield of 79.9 percent and the purity of HPLC: 98.5 percent.
1HNMR(DMSO-d6)：δppm 1.2-1.34(m，1H)，1.37-1.68(m，3H)，1.87-1.95(m，1H)，2.34-2.75(m，5H)，3.04-3.15(ddd，1H)，4.76-4.87(m，1H)，6.98-7.04(m，2H)，7.09-7.12(m，2H)，7.37(brs，1H)，7.46-7.54(m，2H).MS(ESI)350m/z(M+H)+
2. Preparation of the crude aclidinium bromide
58.1g of 2, 2-dithienyl-2-hydroxyacetic acid-R-quinine-3-yl ester (0.17mol), 43g of 3-phenoxybromopropane (0.2mol) and 600ml of acetonitrile are added into a reaction bottle, reflux reaction is carried out for 3 hours, the temperature is reduced to 20-30 ℃, and after filtration, vacuum drying is carried out at 50 ℃ to obtain 87.3g of white solid, the yield is 93%, and the purity is 98.5%.
3. Purification of the crude aclidinium bromide
Adding 4g of crude aclidinium bromide and 40ml of DMF (dimethyl formamide) into a reaction bottle, stirring for 1 hour at 90-100 ℃, dissolving and clarifying, cooling to 0-5 ℃, stirring for 1 hour, dripping 40ml of tetrahydrofuran, continuing stirring for 1 hour after dripping is finished, filtering, and drying in vacuum at 60 ℃ and-0.09 Mpa to obtain 3.3g of white solid, wherein the yield is 82.5%, the purity is 99.1%, and the DMF residue is 0.78%.
Comparative example 5: purification of crude aclidinium bromide
Preparation of 2, 2-dithienyl-2-hydroxyacetic acid-R-quinuclidin-3-yl ester
Adding 50g of 2, 2-dithienyl-2-glycolic acid (0.21mol) and 500ml of DMF (dimethyl formamide) into a reaction bottle, slowly adding 37.45g of CDI (0.23mol) solid, stirring at 15-25 ℃ for 1 hour, then adding 26.7g of R-3-quininol (0.21mol), stirring at 30-35 ℃ for 12 hours, adopting TLC to monitor the complete reaction of the raw materials, cooling to 0-5 ℃ in an ice bath, slowly dropping 500ml of water, stirring at 0-10 ℃ for 0.5 hour after dropping, filtering, and drying in vacuum at 60 ℃ to obtain 58.1g of white-like solid with the yield of 79.9 percent and the purity of HPLC: 98.5 percent.
1HNMR(DMSO-d6)：δppm 1.2-1.34(m，1H)，1.37-1.68(m，3H)，1.87-1.95(m，1H)，2.34-2.75(m，5H)，3.04-3.15(ddd，1H)，4.76-4.87(m，1H)，6.98-7.04(m，2H)，7.09-7.12(m，2H)，7.37(brs，1H)，7.46-7.54(m，2H).MS(ESI)350m/z(M+H)+
2. Preparation of the crude aclidinium bromide
58.1g of 2, 2-dithienyl-2-hydroxyacetic acid-R-quinine-3-yl ester (0.17mol), 43g of 3-phenoxybromopropane (0.2mol) and 600ml of acetonitrile are added into a reaction bottle, reflux reaction is carried out for 3 hours, the temperature is reduced to 20-30 ℃, and after filtration, vacuum drying is carried out at 50 ℃ to obtain 87.3g of white solid, the yield is 93%, and the purity is 98.5%.
3. Purification of the crude aclidinium bromide
Adding 4g of crude aclidinium bromide and 40ml of DMF (dimethyl formamide) into a reaction bottle, stirring for 1 hour at 90-100 ℃, dissolving and clarifying, cooling to 35-40 ℃, stirring for 1 hour, dripping 40ml of dichloromethane, continuing stirring for 1 hour after dripping is finished, filtering, and drying in vacuum at 60 ℃ and-0.09 Mpa to obtain 3.1g of white solid, wherein the yield is 77.5%, the purity is 99.9%, and the DMF residue is 0.18%.
The results of examples 1-6 and comparative examples 1-5 above show that the recrystallization purification process conditions have a significant effect on the purity of the finished aclidinium bromide. The poor crystal growing effect, the excessive solvent residue, the insufficient crystal growing effect caused by the overhigh and overlow crystallization temperature, the small particles and the excessive solvent residue due to the excessively high and overlow DMF solvent amount can cause the insufficient crystal growing effect, the significant influence on the solvent residue of the product can be realized, if the range is exceeded, the DMF residue of the purified aclidinium bromide finished product does not meet the ICH standard (less than 0.088%), the product quality is unqualified (as in comparative examples 1-5), and the medicinal production cannot be carried out.
Comparative example 6: purification of crude aclidinium bromide
Preparation of 2, 2-dithienyl-2-hydroxyacetic acid-R-quinuclidin-3-yl ester
Adding 50g of 2, 2-dithienyl-2-glycolic acid (0.21mol) and 500ml of DMF (dimethyl formamide) into a reaction bottle, slowly adding 37.45g of CDI (0.23mol) solid, stirring at 15-25 ℃ for 1 hour, then adding 26.7g of R-3-quininol (0.21mol), stirring at 30-35 ℃ for 12 hours, adopting TLC to monitor the complete reaction of the raw materials, cooling to 0-5 ℃ in an ice bath, slowly dropping 500ml of water, stirring at 0-10 ℃ for 0.5 hour after dropping, filtering, and drying in vacuum at 60 ℃ to obtain 58.1g of white-like solid with the yield of 79.9 percent and the purity of HPLC: 98.5 percent.
1HNMR(DMSO-d6)：δppm 1.2-1.34(m，1H)，1.37-1.68(m，3H)，1.87-1.95(m，1H)，2.34-2.75(m，5H)，3.04-3.15(ddd，1H)，4.76-4.87(m，1H)，6.98-7.04(m，2H)，7.09-7.12(m，2H)，7.37(brs，1H)，7.46-7.54(m，2H).MS(ESI)350m/z(M+H)+
2. Preparation of the crude aclidinium bromide
58.1g of 2, 2-dithienyl-2-hydroxyacetic acid-R-quinine-3-yl ester (0.17mol), 43g of 3-phenoxybromopropane (0.2mol) and 600ml of acetonitrile are added into a reaction bottle, reflux reaction is carried out for 3 hours, the temperature is reduced to 20-30 ℃, and after filtration, vacuum drying is carried out at 50 ℃ to obtain 87.3g of white solid, the yield is 93%, and the purity is 98.5%.
3. Purification of the crude aclidinium bromide
Adding 4g of crude aclidinium bromide and 40ml of DMSO (dimethyl sulfoxide) into a reaction bottle, stirring for 1 hour at 40-45 ℃, dissolving and clarifying, dropwise adding 80ml of acetonitrile, cooling to 20-25 ℃ after dropwise adding, stirring for 2 hours, filtering, and drying in vacuum at 60 ℃ and-0.09 MPa to obtain 2.5g of white solid, wherein the yield is 62.5%, the purity is 99.3%, and the DMSO residue is 1.3% (0.5% of ICH standard).
Comparative example 7: purification of crude aclidinium bromide
Preparation of 2, 2-dithienyl-2-hydroxyacetic acid-R-quinuclidin-3-yl ester
Adding 50g of 2, 2-dithienyl-2-glycolic acid (0.21mol) and 500ml of DMF (dimethyl formamide) into a reaction bottle, slowly adding 37.45g of CDI (0.23mol) solid, stirring at 15-25 ℃ for 1 hour, then adding 26.7g of R-3-quininol (0.21mol), stirring at 30-35 ℃ for 12 hours, adopting TLC to monitor the complete reaction of the raw materials, cooling to 0-5 ℃ in an ice bath, slowly dropping 500ml of water, stirring at 0-10 ℃ for 0.5 hour after dropping, filtering, and drying in vacuum at 60 ℃ to obtain 58.1g of white-like solid with the yield of 79.9 percent and the purity of HPLC: 98.5 percent.
1HNMR(DMSO-d6)：δppm 1.2-1.34(m，1H)，1.37-1.68(m，3H)，1.87-1.95(m，1H)，2.34-2.75(m，5H)，3.04-3.15(ddd，1H)，4.76-4.87(m，1H)，6.98-7.04(m，2H)，7.09-7.12(m，2H)，7.37(brs，1H)，7.46-7.54(m，2H).MS(ESI)350m/z(M+H)+
2. Preparation of the crude aclidinium bromide
58.1g of 2, 2-dithienyl-2-hydroxyacetic acid-R-quinine-3-yl ester (0.17mol), 43g of 3-phenoxybromopropane (0.2mol) and 600ml of acetonitrile are added into a reaction bottle, reflux reaction is carried out for 3 hours, the temperature is reduced to 20-30 ℃, and after filtration, vacuum drying is carried out at 50 ℃ to obtain 87.3g of white solid, the yield is 93%, and the purity is 98.5%.
3. Purification of the crude aclidinium bromide
Adding 4g of crude aclidinium bromide and 40ml of DMSO (dimethyl sulfoxide) into a reaction bottle, stirring for 1 hour at 40-45 ℃, dissolving and clarifying, dripping 80ml of isopropanol, cooling to 20-25 ℃ after dripping, stirring for 2 hours, filtering, and drying in vacuum at 60 ℃ and-0.09 MPa to obtain 1.9g of white solid, wherein the yield is 47.5%, the purity is 99.1%, and the DMSO residue is 1.2% (0.5% of ICH standard).
Comparative example 8: purification of crude aclidinium bromide
Preparation of 2, 2-dithienyl-2-hydroxyacetic acid-R-quinuclidin-3-yl ester
Adding 50g of 2, 2-dithienyl-2-glycolic acid (0.21mol) and 500ml of DMF (dimethyl formamide) into a reaction bottle, slowly adding 37.45g of CDI (0.23mol) solid, stirring at 15-25 ℃ for 1 hour, then adding 26.7g of R-3-quininol (0.21mol), stirring at 30-35 ℃ for 12 hours, adopting TLC to monitor the complete reaction of the raw materials, cooling to 0-5 ℃ in an ice bath, slowly dropping 500ml of water, stirring at 0-10 ℃ for 0.5 hour after dropping, filtering, and drying in vacuum at 60 ℃ to obtain 58.1g of white-like solid with the yield of 79.9 percent and the purity of HPLC: 98.5 percent.
1HNMR(DMSO-d6)：δppm 1.2-1.34(m，1H)，1.37-1.68(m，3H)，1.87-1.95(m，1H)，2.34-2.75(m，5H)，3.04-3.15(ddd，1H)，4.76-4.87(m，1H)，6.98-7.04(m，2H)，7.09-7.12(m，2H)，7.37(brs，1H)，7.46-7.54(m，2H).MS(ESI)350m/z(M+H)+
2. Preparation of the crude aclidinium bromide
58.1g of 2, 2-dithienyl-2-hydroxyacetic acid-R-quinine-3-yl ester (0.17mol), 43g of 3-phenoxybromopropane (0.2mol) and 600ml of acetonitrile are added into a reaction bottle, reflux reaction is carried out for 3 hours, the temperature is reduced to 20-30 ℃, and after filtration, vacuum drying is carried out at 50 ℃ to obtain 87.3g of white solid, the yield is 93%, and the purity is 98.5%.
3. Purification of the crude aclidinium bromide
Adding 4g of crude aclidinium bromide and 40ml of acetonitrile into a reaction bottle, refluxing and stirring for 1 hour to ensure that the crude aclidinium bromide is not dissolved and clarified, cooling to 20-25 ℃, stirring for 2 hours, filtering, and drying in vacuum at 60 ℃ and-0.09 Mpa to obtain 3.9g of white solid, wherein the yield is 97.5%, the purity is 98.9%, and the acetonitrile residue is 0.01% (0.041% of ICH standard).
Comparative example 9: purification of crude aclidinium bromide
Preparation of 2, 2-dithienyl-2-hydroxyacetic acid-R-quinuclidin-3-yl ester
Adding 50g of 2, 2-dithienyl-2-glycolic acid (0.21mol) and 500ml of DMF (dimethyl formamide) into a reaction bottle, slowly adding 37.45g of CDI (0.23mol) solid, stirring at 15-25 ℃ for 1 hour, then adding 26.7g of R-3-quininol (0.21mol), stirring at 30-35 ℃ for 12 hours, adopting TLC to monitor the complete reaction of the raw materials, cooling to 0-5 ℃ in an ice bath, slowly dropping 500ml of water, stirring at 0-10 ℃ for 0.5 hour after dropping, filtering, and drying in vacuum at 60 ℃ to obtain 58.1g of white-like solid with the yield of 79.9 percent and the purity of HPLC: 98.5 percent.
1HNMR(DMSO-d6)：δppm 1.2-1.34(m，1H)，1.37-1.68(m，3H)，1.87-1.95(m，1H)，2.34-2.75(m，5H)，3.04-3.15(ddd，1H)，4.76-4.87(m，1H)，6.98-7.04(m，2H)，7.09-7.12(m，2H)，7.37(brs，1H)，7.46-7.54(m，2H).MS(ESI)350m/z(M+H)+
2. Preparation of the crude aclidinium bromide
58.1g of 2, 2-dithienyl-2-hydroxyacetic acid-R-quinine-3-yl ester (0.17mol), 43g of 3-phenoxybromopropane (0.2mol) and 600ml of acetonitrile are added into a reaction bottle, reflux reaction is carried out for 3 hours, the temperature is reduced to 20-30 ℃, and after filtration, vacuum drying is carried out at 50 ℃ to obtain 87.3g of white solid, the yield is 93%, and the purity is 98.5%.
3. Purification of the crude aclidinium bromide
Adding 4g of crude aclidinium bromide and 80ml of ethanol into a reaction bottle, refluxing and stirring for 1 hour to ensure that the crude aclidinium bromide is not dissolved and clarified, cooling to 0-5 ℃, stirring for 2 hours, filtering, and drying in vacuum at 60 ℃ and-0.09 Mpa to obtain 2.7g of white solid, wherein the yield is 67.5%, the purity is 99.4%, and the ethanol residue is 0.08% (0.5% of ICH standard).
As can be seen from the comparative examples 6-9, the excessive solvent residue is obvious when DMSO is used as the solvent, and the yield is low when other solvents are used, and the solvents cannot be dissolved clearly during recrystallization, so that the impurities are not removed favorably.
Claims (16)
1. A recrystallization purification method of choline M receptor anticaking agent aclidinium bromide comprises the following steps:
(1) heating the aclidinium bromide crude product and DMF to 90-130 ℃, stirring, dissolving and clarifying;
(2) cooling the solution obtained in the step (1) to 60-80 ℃, adding an aclidinium bromide seed crystal, wherein the addition amount of the aclidinium bromide seed crystal is 1-5% of the weight of the solution obtained in the step (1), and stirring for 1-5h under heat preservation;
(3) cooling the solution obtained in the step (2) to 40-80 ℃, then dripping an anti-solvent into the solution, then cooling to 0-40 ℃, stirring, filtering and drying in vacuum;
wherein the proportion of the DMF to the aclidinium bromide crude product is 8-15 ml: 1g of a compound;
the anti-solvent is one or more selected from dichloromethane, ethyl acetate, acetonitrile and tetrahydrofuran.
2. The recrystallization purification method according to claim 1, wherein the ratio of the DMF to the crude adefovir dipivoxil is 10 ml: 1g of the total weight of the composition.
3. The recrystallization purification method according to claim 1, wherein in the step (1), the heating is performed to 90 to 100 ℃.
4. The recrystallization purification method according to claim 1, wherein the stirring time in step (1) is 0.5 to 1.5 hours.
5. The recrystallization purification method according to claim 1, wherein the stirring time in the step (1) is 1 hour.
6. The recrystallization purification method according to claim 1, wherein the temperature of the solution obtained in the step (1) is reduced to 75-80 ℃.
7. The recrystallization purification method according to claim 1, wherein the stirring time under heat is 1 hour.
8. The recrystallization purification method according to claim 1, wherein in the step (3), the temperature of the solution obtained in the step (2) is reduced to 40-45 ℃, and then an anti-solvent is added dropwise.
9. The recrystallization purification method according to claim 1, wherein in the step (3), the temperature is continuously reduced to 20 to 30 ℃ after the anti-solvent is dropped.
10. The recrystallization purification method according to claim 1, wherein the stirring time in the step (3) is 0.5 to 1.5 hours.
11. The recrystallization purification method according to claim 1, wherein the stirring time in the step (3) is 1 hour.
12. The recrystallization purification method according to claim 1, wherein in the step (3), the filtration means is vacuum filtration.
13. The recrystallization purification method according to claim 1, wherein the temperature of the vacuum drying in the step (3) is 55 to 65 ℃.
14. The recrystallization purification method according to claim 1, wherein the temperature of the vacuum drying in the step (3) is 60 ℃.
15. The recrystallization purification method according to claim 1, wherein the degree of vacuum in the step (3) is from-0.8 to-0.1 MPa.
16. The recrystallization purification process according to any one of claims 1 to 15, comprising the steps of:
(1) heating the aclidinium bromide crude product and DMF to 90-100 ℃, stirring for 1h, dissolving and clarifying; wherein the ratio of the DMF to the crude adefovir dipivoxil is 10 ml: 1g of a compound;
(2) cooling the solution obtained in the step (1) to 75-80 ℃, adding an aclidinium bromide seed crystal, and stirring for 1 h; wherein the addition amount of the aclidinium bromide seed crystal is 1-5% of the weight of the solution obtained in the step (1);
(3) and (3) cooling the solution obtained in the step (2) to 40-45 ℃, then dripping an anti-solvent, then continuously cooling to 20-30 ℃, stirring for 1h, carrying out vacuum filtration, and carrying out vacuum drying at 60 ℃ and-0.8-0.1 Mpa to obtain the pure aclidinium bromide.
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| WO2015071824A1 (en) * | 2013-11-13 | 2015-05-21 | Glenmark Pharmaceuticals Limited; Glenmark Generics Limited | Process for the preparation of aclidinium bromide |
| CN104478871A (en) * | 2014-12-26 | 2015-04-01 | 东华大学 | Choline M receptor antagonist aclidinium bromide and preparation method thereof |
| CN108112252A (en) * | 2015-03-30 | 2018-06-01 | 好利安科技有限公司 | The method for preparing aclidinium bromide |
| CN106831756A (en) * | 2017-01-04 | 2017-06-13 | 广州迈达康医药科技有限公司 | A kind of high-purity high-yield is adapted to the aclidinium bromide preparation method of industrialized production |
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